| Extracellular RNA-TLR3 Axis in Hypoxia-Induced Myocardial Injury: A Potential Therapeutic Target |
| Paper ID : 1229-IGA |
| Authors |
|
Gausal Azam Khan * King Faisal University |
| Abstract |
| Acute hypoxia (AH), commonly encountered during high-altitude exposure or pathological ischaemia, induces significant myocardial injury through inflammatory and immunological cascades. This study investigates the mechanistic role of extracellular RNA (eRNA) in hypoxia-induced myocardial infarction (MI), focusing on the Toll-like receptor 3 (TLR3)-caspase-3 pathway in a murine model. Exposure to hypoxic conditions resulted in a time-dependent elevation of cardiac injury biomarkers, notably cardiac troponin-T (cTrop-T) and myoglobin, indicating progressive myocardial damage. ELISA-based quantification confirmed that RNaseA, an RNA-degrading enzyme, significantly suppressed the hypoxia-induced increase in plasma cTrop-T, while DNase1 and HMGB1-neutralising antibodies showed no effect, underscoring the specific involvement of eRNA. Further analysis demonstrated that eRNA acts through TLR3 to facilitate cTrop-T release. TLR3 blockade, both through immunoneutralization and siRNA-mediated gene silencing, significantly mitigated this effect, confirming its central role. Histological assessments revealed that AH-induced eRNA contributes to cardiac collagen accumulation and robust leukocyte infiltration, as evidenced by increased expression of α-SMA, CD31, NE, MAC-1, and CD41. These pathological changes were reversed with RNaseA pre-treatment, indicating that eRNA is a critical DAMP responsible for myocardial inflammation and remodelling. Additionally, AH and eRNA stimulation triggered caspase-3 activation, a hallmark of programmed necrosis, which was effectively abrogated by TLR3 inhibition and RNaseA administration. This highlights the caspase-3 pathway as a downstream effector of TLR3-eRNA signalling in myocardial injury. In conclusion, this study elucidates a novel inflammatory axis involving hypoxia-induced eRNA, TLR3 activation, and caspase-3-mediated myocardial damage. Targeting this pathway using RNaseA or TLR3 inhibitors may offer promising therapeutic strategies for preventing hypoxia-induced acute myocardial infarction and related cardiovascular complications. |
| Keywords |
| Hypoxia, Myocardial Injury, cTrop-T, Extracellular RNA, TLR3, Caspase-3, Inflammation, Acute High Altitude, RNaseA |
| Status: Accepted |
